Crystal structure of a phospholipase A2 from Bothrops asper venom: Insights into a new putative “myotoxic cluster”
artículo original
Fecha
2017Autor
Salvador, Guilherme Henrique Marchi
dos Santos, Juliana
Lomonte, Bruno
Fontes, Marcos Roberto de Mattos
Metadatos
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Snake venoms from the Viperidae and Elapidae families often have several phospholipases A2 (PLA2s),
which may display different functions despite having a similar structural scaffold. These proteins are
considered an important target for the development of drugs against local myotoxic damage because
they are not efficiently neutralized by conventional serum therapy. PLA2s from these venoms are
generally divided into two classes: (i) catalytic PLA2s (or Asp49-PLA2s) and (ii) non-catalytic PLA2-like
toxins (or Lys49-PLA2s). In many Viperidae venoms, a subset of the basic Asp49-PLA2s displays some
functional and structural characteristics of PLA2-like proteins and group within the same phylogenetic
clade, but their myotoxic mechanism is still largely unknown. In the present study, we have crystallized
and solved the structure of myotoxin I (MT-I), a basic myotoxic Asp49-PLA2 isolated from Bothrops asper
venom. The structure presents a dimeric conformation that is compatible with that of previous dimers
found for basic myotoxic Asp49-PLA2s and Lys49-PLA2s and has been confirmed by other biophysical and
bioinformatics techniques. This arrangement suggests a possible cooperative action between both
monomers to exert myotoxicity via two different sites forming a putative membrane-docking site
(MDoS) and a putative membrane disruption site (MDiS). This mechanism would resemble that proposed
for Lys49-PLA2s, but the sites involved appear to be situated in a different region. Thus, as both sites are
close to one another, they form a “myotoxic cluster”, which is also found in two other basic myotoxic
Asp49-PLA2s from Viperidae venoms. Such arrangement may represent a novel structural strategy for the
mechanism of muscle damage exerted by the group of basic, Asp49-PLA2s found in viperid snake
venoms.
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10.1016/j.biochi.2016.12.015Colecciones
- Microbiología [1171]